Taxonomic Applicability

Sex Applicability

Life Stage Applicability

Key Event Relationship Description

Under physiological conditions, in the developing nervous system, apoptosis occurs during the process of synaptogenesis, where competition leads to the loss of excess neurons and to the connection of the appropriate neurons (Buss et al., 2006; Mennerick and Zorumski, 2000; Oppenheim, 1991). However, when a stressor increases the number of apoptotic cells this KE has a negative effect on synaptogenesis as the reduced number of neurons (besides the ones that have been already eliminated through the physiological process of apoptosis) provides limited dendritic fields for receiving synaptic inputs from incoming axons. At the same time the loss of neurons also means that there are less axons to establish synaptic contacts (Olney, 2014), leading to reduced synaptogenesis and neuronal networking.

Evidence Supporting this KER

Biological Plausibility

Recently, Dekkers et al. 2013 have reviewed how under physiological conditions components of the apoptotic machinery in developing brain regulate synapse formation and neuronal connectivity. For example, caspase activation is known to be required for axon pruning during development to generate neuronal network (reviewed in Dekkers et al., 2013). Experimental work carried out in Drosophila melanogaster and in mammalian neurons shows that components of apoptotic machinery are involved in axonal degeneration that can consequently interfere with synapse formation (reviewed in Dekkers et al., 2013). Furthermore, Bax mutant mice studies indicate that the lack of this pro-apoptotic protein BAX leads to disruption of intrinsically photosensitive retinal ganglion cells spacing and dendritic stratification that affects synapse localization and function (Chen et al., 2013).

Empirical Evidence

Synaptogenesis and refinement of the cortical network precedes the programmed cells death of neurons during development (Innocenti and Price, 2005).

Pb2+: Elevated blood Pb2+ concentrations that have been evident in new-born rats prenatally exposed to 30 or 200 mg/l Pb2+ caused postnatally delay in synaptogenesis (McCauley et al., 1982). In this study, Pb2+ treatment depresses synaptic counts in pups of PND 11 to 15 but not in older pups (McCauley et al., 1982). In rat hippocampal primary cultures, Pb2+ treatment has no effect on PSD95 puncta density nor has any effect on Synapsin Ia/b total gray value, puncta density, and integrated intensity but only reduces the phosphorylation of Synapsin Ia/b (Stansfield et al., 2012). Pb2+ exposure also represses the expression of presynaptic vesicular proteins implicated in neurotransmitter release, such as synaptobrevin (VAMP1) and synaptophysin (SYN) (Neal et al., 2010). In mouse ESCs cultured in 3D aggregates, the treatment with 0.1 µM Pb2+ causes around 25% of cell loss that is not attributed to apoptosis as no change in caspase 3 levels has been detected (Sánchez-Martín et al., 2013). In the same study but in an in vivo model, Pb2+ causes downregulation of Syn1 gene expression in the hippocampus of male offspring (PND 60) derived from female mice exposed to 0 or 3 ppm of lead acetate in drinking water from 8 weeks prior to mating, through gestation and until PND 10 (Sánchez-Martín et al., 2013).

Uncertainties and Inconsistencies

In adult nervous system, the role of apoptotic machinery in axon pruning and synapse elimination, which are necessary to refine mature neuronal network has been extensively studied (reviewed in Hyman and Yuan, 2012), whereas in developing nervous system the regulatory importance of apoptotic machinery in synapse formation and function is less clear (reviewed in Dekkers et al., 2013).

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second?
Are there known modulators of the response-response relationships?
Are there models or extrapolation approaches that help describe those relationships?

No enough data is available to address the questions above.

Response-response Relationship

Time-scale

Known modulating factors

Known Feedforward/Feedback loops influencing this KER

Domain of Applicability

Experiments have been conducted both in Drosophila melanogaster and in mammals in order to elucidate the relationship between components of apoptotic machinery and synaptogenesis (reviewed in Dekkers et al., 2013).